Autoimmune diseases are a type of immune pathologies that result from an uncontrolled immune response against autoantigens. The susceptibility to autoimmune diseases is affected by gender. During reproductive ages, there exists a prevalence among females to suffer from an autoimmune disease such as multiple sclerosis (MS) or rheumatoid arthritis (RA). For example, the female-to-male ratio to develop MS is 2:1 (Voskuhl et al., 2001; Neuroscientist 7: 258-270; Whitacre et al., 1999; Science 283: 1277-1278).
MS is an autoimmune disorder of the central nervous system affecting the myelin sheath of neurons and leading to demyelination and subsequent neuronal cell death. The disease is mediated by CD4+ T lymphocytes, which are specific for proteins in the myelin sheath like myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte protein. One hypothesis is that on the basis of a genetically determined predisposition, environmental factors such as viral infections trigger the outbreak of the disease which results in an imbalance in the Th1 and Th2 population of lymphocytes, thereby promoting the accumulation of activated Th1 cells that are able to penetrate the blood-brain barrier and exert proinflammatory actions in the CNS. Demyelination of axons is in part caused by myelin-specific CD4+ lymphocytes secreting Th1 cytokines like interleukin(IL)-12, interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). This pro-inflammatory cytokine pattern is characteristic for the cell-mediated immune response. In healthy individuals the cell-mediated Th1 immune response is in balance with the humoral Th2 immune response.
The humoral immune response is mediated by the anti-inflammatory Th2 cytokines IL-4, IL-5 and IL-10.
The treatment strategies of MS are currently based on immunomodulatory treatment using interferons or glatiramer acetate. However, these treatments delay progress of disease only in some patients. Corticosteroids are used for acute treatment of relapses due to their antiinflammatory effects. Treatment with corticosteroids alleviates some acute symptoms of MS but fails to affect long-term prognosis. In addition to the known, numerous side-effects of corticosteroids, they also inhibit endogenous immunosuppressive mechanisms, rendering them unsuitable for long-term therapy. For therapy of highly active disease or of patients not responding to standard treatments including patients suffering from secondary progressive MS, immunosuppressive agents like methotrexate or cyclosporine are used. These substances are often poorly tolerated.
Therefore, there exists a need for an additional treatment strategy of MS and other Th1-mediated immune diseases.
In many autoimmune diseases, such as in MS, the Th1/Th2 balance is disturbed. Female sex hormones seem to have an influence on the regulation of this balance. During pregnancy, a shift toward a Th2 cytokine pattern has been demonstrated. An improvement of the clinical symptoms of Th1-mediated immune diseases (like MS) during pregnancy has also been observed. Especially in the third trimester of pregnancy, the rate of relapse declines in women with MS (Confavreux et al., 1998; N Engl J Med 339(5): 285-291). The decrease in disease activity appears to be due at least in part to high levels of estrogens such as estradiol and estriol, which are observed during the last trimester of pregnancy. In an animal model of MS, the Th1-mediated experimental autoimmune encephalomyelitis (EAE), it has been shown that administration of estriol at levels equal to those found in pregnancy were capable of ameliorating disease (Kim et al., 1999; Neurology 52: 1230-1238; Jansson et al., 1994, J Neuroimmunol 53: 203-207). Furthermore, it has been shown by Correale et al. (1998: J Immunol 161: 3365-3374) that the secretion of the anti-inflammatory cytokine IL-10 by CD4+ lymphocytes of MS patients is stimulated by estradiol, estrone and estriol at concentrations at a similar level as in pregnancy.
WO 01/85154 discloses a method of treating immune pathologies with low dose estrogen raising the serum concentration above basal level, but below pregnancy levels.
Because of the involvement of estrogens in the regulation of the balance between pro-inflammatory and anti-inflammatory conditions, a potential therapy for patients suffering from a Th1-mediated immune disease is to administer estrogens, in particular estriols, preferably to achieve continuous serum concentrations typically found in pregnancy.
However, the therapeutic use of estrogens is afflicted with several problems. One disadvantage of the use of estrogens in therapy is their potential ability to cause uterine cancer (endometrium carcinoma) or breast cancer. For example, the use of estradiol could lead to the metabolite 16alpha-hydroxyestrone, a metabolite with known tumor-promoting activity (Bradlow et al., 1985; Proc Natl Sci USA 82: 6295-6299; Kabat et al., 1997; Cancer Epidemiol Biomarkers Prev 6: 505-509).
Estriol as an active principle circumvents this problem. It is believed that estriol therapy is associated with small risks of cancer development in the human. Because of the much faster dissociation of estriol-estrogen receptor (ER) complexes than the dissociation of estradiol-ER complexes, estriol acts as a weaker and only short lasting estrogen. Therefore, estriol causes minimal endometrial proliferation. In addition, estriol displays antagonistic activity on the binding of estradiol to the receptor (Clark et al, 1984; J Steroid Biochem 20: 1005-1013) and therefore estriol seems to have a protective role opposing carcinogenic effects of estradiol. The antagonistic effects of estriol are only observed if the ratio of estriol to estradiol and estrone is 10:1, below this ratio estradiol is only partially or minimally antagonized and acts as a potent estrogen (Melamed et al, 1997; Mol Endocrinol 11: 1868-1878). This ratio is achieved in late pregnancy.
One problem encountered in the prior art is the inability to achieve continuous pregnancy blood levels of estriol with a form of administration that is comfortable for the patient. When administered orally, the bioavailability of estriol is low. To achieve comparable serum levels of estriol as after intravaginal application, ten times more estriol had to be administered orally (Head et al., 1998. Altern Med Rev 3: 101-113). Thus, estriol had to be orally administered in high doses, giving rise to possible side effects. Oral application of estriol leads to high estrogenicity in the liver. Hepatic effects include, for example, the increased synthesis of factors of the blood clotting system and angiotensinogen.
Another problem known from the prior art for oral therapy with estriol is that blood levels of estriol vary widely from patient to patient, so that general recommendations of the doses are not possible.
Problematic is also the very short half-life of estriol of about 1.5-5.3 h (Heithecker et al., 1991; Horm Res 35: 234-238). Thus, to achieve well-defined and sustained blood levels of estriol similar to those found in pregnancy, high doses of oral estriol would have to be administered at short time intervals which is not convenient for the patient, and several side effects have to be taken into account.
Increase of the orally administered dose of estriol is not the way to increase the desired systemic estrogenicity. Osteoprotective properties of estriol are a quite good marker for the systemic estrogenicity of estriol. EP 0 630 248 teaches that if estriol is administered transdermally in a system which continuously releases estriol for at least 24 h and thereby a constant blood level of estriol is achieved, estriol exhibits anti-osteoporotical effects. The decisive factor for these effects is the constant estriol blood level. Although Lindsay et al. (1979; Maturitas 1: 279-285) administered orally estriol in very high doses (12 mg/day), they were not able to show the osteoprotective effects.
EP 0 163 596 discloses estra-1,3,5(10)-triene ester derivatives, methods of preparing such compounds and pharmaceutical compositions containing them.
In view of the problems encountered by the prior art, a new therapeutic approach for the treatment of autoimmune diseases by achieving a well-defined and sustained blood level of estriol without the described disadvantages would be desirable.